Given that atherosclerosis is so common in diabetes and given that cholesterol metabolism is so closely involved with atherosclerosis, this project is designed to investigate sterol metabolism in diabetes. Specifically we propose to investigate cholesterol absorption, the pattern of fecal sterol excretion and particularly the effect of insulin on cholesterol synthesis in diabetes. Methods which will be applied to diabetics include chemical sterol balance, isotopically labeled cholesterol turnover and a new method capable of measuring cholesterol synthesis over a ten hour period. The latter involves intravenous injection of 14C-mevalonic acid with observation of 14C-squalene appearance and die-away into 14C-cholesterol. The effect of insulin on cholesterol synthesis will be determined by combined chemical balance and 14C-mevalonate infusion in patients hospitalized on our Clinical Research Center for three month periods; another set of patients will have insulin and glucose infusions during the mevalonate infusion test; and particular subgroups of diabetics will be studied with mevalonate infusions during brief hospitalization. Squalene metabolism will also be studied in hypertriglyceridemia, a commonly found hyperlipidemia in diabetes and one which may affect cholesterol synthesis. All proposed studies are to be carried out in human volunteers. The overall objective is to enhance our understanding of atherosclerosis in diabetes.